ES2336719T3 - FLIBANSERINE FOR THE TREATMENT OF URINARY INCONTINENCE AND RELATED DISEASES. - Google Patents

Abstract

The invention relates to the use of Flibanserin for the treatment or prevention of urinary incontinence and related diseases. In a further embodiment, the instant invention is directed to pharmaceutical combinations comprising flibanserin as one active ingredient in combination with at least one additional active ingredient for the treatment or prevention of urinary incontinence and related diseases.

Description

Flibanserin for the treatment of urinary incontinence and related diseases.

The present invention relates to the use of the flibanserin for the treatment or prevention of incontinence  Urinary and related diseases. In an additional way of presentation, the present invention, is directed to the use of pharmaceutical combinations, which comprise flibanserin as an active ingredient, in combination with at least one additional active ingredient for the treatment or prevention of urinary incontinence and related diseases.

Description of the invention

The compound 1- [2- (4- (3-Trifluoromethyl-phenyl) piperazin-1-yl) ethyl] -2,3-dihydro-1H-benzimidazol-2-one  (flibanserin), is disclosed in the form of its hydrochloride, in European patent application EP-A 526 434, and has the following chemical structure:

one

Flibanserin shows affinity for 5-HT1A and 5-HT12 receptor. This is, therefore, a promising therapeutic agent, for the treatment or the prevention of a variety of diseases, such as for depression, schizophrenia and anxiety.

Now, experiments that have been done, have provided evidence as to the fact that, the flibanserin, cannot only be used for diseases previously mentioned, above, but, in addition, this one can be used for the treatment or prevention of incontinence urinary

In a form of presentation, the present invention, refers to the use of a therapeutically amount effective flibanserin 1, optionally, in the form of the base free, pharmacologically acceptable acid addition salts and / or optionally, in the form of hydrates and / or solvates thereof, for the treatment or prevention of incontinence urinary

With respect to the present invention, the term "urinary incontinence" includes urinary incontinence for stress, urgent urinary incontinence, the combination of urinary incontinence and overactive bladder syndrome.

Urinary incontinence (UI - [from English, urinary incontinence] -), like other lower dysfunctions of the urinary tract, can be described as a symptom, or as a sign, as a urodynamic observation or as a condition, as a whole The symptom of the UI is defined as "the disease consisting of any involuntary dripping of urine "(Abrams P. Cardozo Neurourol Urodyn 2002; 21: 167-178).

Stress urinary incontinence (SUI - [of English, incontinent urinary Stress-], is defined as the disease consisting of an involuntary drip, due to an effort or a excessive work, or a sneeze or cough. This happens due to fact that, a positive urethral pressure gradient, above of bladder pressure, cannot be maintained for increments abrupt abdominal pressure. This insufficient urethral pressure of closure, may not be the consequence of anatomical defects in the pelvic floor muscles, leading to hypermobility urethral, intrinsic deficiency of the external urethral sphincter, or a A combination of both.

SUI is more common in women than in the men. In the pregnancy of women, in childbirth and parity, are the most important initiation factors. In the men, the SUI, is uncommon and, most of the time, it refers to a sequel after prosthetic surgery (recession transurethral prostate, for benign hyperplasia of prostate, or radical prostatectomy, for prostate cancer). The stress urinary incontinence, is the most common type of UI, in women, presenting, in a percentage of 78% of women with the symptom of SUI, in its pure form (49%) or in its form combined (29%).

Urinary incontinence urgent (UUI - [del English, Urge urinary incontinence] -), is defined as the disease of an involuntary drip, accompanied by an emergency, or immediately preceded by an urgency. The urgency is the disease or illness consisting of a compulsive desire to pass urine, which can be difficult to postpone.

Urgent urinary incontinence is one of the symptoms that are classified under the symptom of the overactive bladder (OAB - [of the English syndrome of Overactive Bladder] -). In concordance with the definition of the ICS, the OAB, it is characterized by a need irresistibly imperative to urinate, which can be found associated, or not, with urgent urinary incontinence, usually, with an increased frequency of urination, and urination nocturnal In a pathophysiological way, this ailment or disease, may be based on involuntary detrusor contractions, during the filling phase, being able to be, the causes of these, neurogenic or non-neurogenic (idiopathic) by nature. The urgency urinary and urgent urinary incontinence, are extremely uncomfortable and problematic, for the people affected, driving to a considerable deterioration of their quality of life to problems physiological, professional, domestic, physical and sexual.

Combined urinary incontinence is defined such as illness or disease consisting of an involuntary drip associated with urgency and also with excessive work, the effort, sneezing or coughing. Also, again, it women are more affected than men.

In another form of presentation of this invention, this refers to the use of a sufficient quantity effective flibanserin 1, optionally, in the form of the base free, pharmacologically acceptable acid addition salts and / or optionally, in the form of hydrates and / or solvates thereof, for the manufacture of a medicament for the treatment or the prevention of overactive bladder syndrome.

In another form of presentation of this invention, this refers to the use of a sufficient quantity effective flibanserin 1, optionally, in the form of the base free, pharmacologically acceptable acid addition salts and / or optionally, in the form of hydrates and / or solvates thereof, for the manufacture of a medicament for the treatment or the Urinary incontinence prevention urgent.

In another form of presentation of this invention, this refers to the use of a sufficient quantity effective flibanserin 1, optionally, in the form of the base free, pharmacologically acceptable acid addition salts and / or optionally, in the form of hydrates and / or solvates thereof, for the manufacture of a medicament for the treatment or the emergency prevention

In another form of presentation of this invention, this refers to the use of a sufficient quantity effective flibanserin 1, optionally, in the form of the base free, pharmacologically acceptable acid addition salts and / or optionally, in the form of hydrates and / or solvates thereof, for the manufacture of a medicament for the treatment or the prevention of stress urinary incontinence.

In another form of presentation of this invention, this refers to the use of a sufficient quantity effective flibanserin 1 optionally, in the form of the free base, pharmacologically acceptable acid addition salts and / or optionally, in the form of hydrates and / or solvates thereof, to the manufacture of a medication for treatment or Combined urinary incontinence prevention.

Since, flibanserin 1 can be used not only as a monotherapy, but also in combination with other active ingredients, for the treatment of continence urinary, another method of the present invention, refers to the new use of pharmaceutical compositions, which comprise a sufficiently effective amount of flibanserin 1 optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates and / or solvates thereof, as an active ingredient, in combination with a therapeutically effective amount of one or more active ingredients, preferably one, consisting of the active ingredient 2, useful for the treatment of urinary incontinence

The composition in accordance with this invention, may contain flibanserin 1 and one or more additional active component (s) consisting (s) in active ingredient 2, in a formulation individually or in separate formulations (dosage form multiple). If flibanserin 1 and the one or more component (s) additional asset (s) consistent in the active ingredient 2, are present in formulations separated, then, these separate formulations, can administered separately or sequentially.

In an additional form of presentation of the present invention, this is directed to the use of a composition pharmaceutical, which comprises a sufficiently effective amount of flibanserin 1, optionally, in the form of the free base, salts for the addition of pharmacologically acceptable acids and / or optionally, in the form of hydrates and / or solvates thereof, as an active ingredient, in combination with an amount therapeutically effective of one or more active ingredients, preferably one, consisting of active ingredient 2, for the manufacture of a medicine useful for the treatment of urinary incontinence, where, 2, is selected from the group consisting of antimuscarinic agents 2a, agonists of the vasopressin 2b, serotonin / noradrenaline 2c modulators and β3 2d agonists.

In an additional form of presentation of the This invention, this one, is directed to the aforementioned use,  above, of a pharmaceutical composition, comprising an amount sufficiently effective flibanserin 1, optionally, in form of the free base, pharmacologically acid addition salts acceptable and / or optionally, in the form of hydrates and / or solvates of this, as an active ingredient, in combination with a therapeutically effective amount of one or more ingredients antimuscarinics, preferably one, consisting of the antimuscarinic ingredient 2a, optionally, in form its salts pharmaceutically acceptable, in the form of hydrates and / or solvates and, optionally, in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates thereof and, optionally, in combination with an acceptable excipient. The 2a preferred antimuscarinic agents, include tolterodine, oxybutynin, darifenacin, proviverine, solifenacin and The trospium

In an additional form of presentation of the This invention, this one, is directed to the aforementioned use,  above, of a pharmaceutical composition, comprising an amount sufficiently effective flibanserin 1, optionally, in form of the free base, pharmacologically acid addition salts acceptable and / or optionally, in the form of hydrates and / or solvates of this, as an active ingredient, in combination with a therapeutically effective amount of one or more agonists of vasopressin, preferably one, consisting of the agonist of vasopressin 2b, optionally, in its pharmaceutically active form acceptable, in the form of hydrates and / or solvates and, optionally, in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates of these and, optionally, in combination with an acceptable excipient. A vasopressin agonist 2b preferred is desmopressin.

In an additional form of presentation of the This invention, this one, is directed to the aforementioned use,  above, of a pharmaceutical composition, comprising an amount sufficiently effective flibanserin 1, optionally, in form of the free base, pharmacologically acid addition salts acceptable and / or optionally, in the form of hydrates and / or solvates of this, as an active ingredient, in combination with a therapeutically effective amount of one or more modulators of serotonin / norepinephrine, preferably one, consisting of the serotonin / noradrenaline modulator 2c, optionally, in its form pharmaceutically acceptable salts, in the form of hydrates and / or solvates and, optionally, in the form of the optical isomers individual, mixtures of the individual enantiomers or racemates of these and, optionally, in combination with an excipient acceptable. Serotonin / noradrenaline 2c modulators Preferred include venlafaxine, duloxelin, reboxetine, and cizoliritine.

In an additional form of presentation of the This invention, this one, is directed to the aforementioned use,  above, of a pharmaceutical composition, comprising an amount sufficiently effective flibanserin 1, optionally, in form of the free base, pharmacologically acid addition salts acceptable and / or optionally, in the form of hydrates and / or solvates of this, as an active ingredient, in combination with a therapeutically effective amount of one or more β3 agonists, preferably one, consisting of the β3 2d agonist, optionally, in the form of its pharmaceutically acceptable salts, in form of hydrates and / or solvates and, optionally, in the form of individual optical isomers, mixtures of the enantiomers or individual racemates of these and, optionally, in combination with An acceptable excipient. Preferred β3 agonists, include AD9677 / TAK677, CL 316,243, SB 418790, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, trecanidine, Zeneca D7114, SR 59119, solabegron, CL616243, acid 2- [4 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] ethyl) phenoxy] 2-methylpropionic, BRL37344A and DGP-12177A.

Flibanserin 1, can optionally be used in the form of its acid addition salts, pharmaceutically acceptable. Acid addition salts appropriate, include, for example, those of acids selected from succinic acid, hydrobromic acid, acid acetic acid, fumaric acid, maleic acid, methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulfuric acid, tartaric acid and citric acid. Mixtures may also be used. of the acid addition salts mentioned above. Among the acid addition salts mentioned above, above, hydrochloric acid and hydrobromic acid are preferred, with particular preference being given to hydrochloric acid. Whether use flibanserin, in the form of the free base, it is used, preferably, in polymorphic flibanserin A form, such and as disclosed in the international patent publication WO 03/014 079.

The active ingredients 2a that are appropriate to be combined with 1, within the teachings of the present invention, and which have been mentioned above, above, can also be able to form acid addition salts, with pharmaceutically acceptable acids. Representative salts, include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisilato, estolato, esilato, fumarate, gluceptate, gluconato, glutamate, glycylolilarsanilate, hexylresorcinate, hydrabamine, bromidrate, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsilate, nitrate, ammonium salt of N-methylglucamine, oleate, oxalate, pamoate (embonate), palmitate, pantoenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tanate, tartrate, teoclate, tosylate, tritiodide and valerate.

Additionally, in addition, where compounds carry 2, an acidic portion, pharmaceutically salts Acceptable thereof, may include alkali metal salts, such as sodium and potassium salts; metal salts alkaline and alkaline earth, such as magnesium salts, and salts formed with appropriate organic ligands, such as quaternary ammonium salts

Compounds 2 may have centers surgical, or be available as racemates, mixtures racemic and as its individual diastereomers or anantiomers. Thus, therefore, where a compound is chirical, the separate enantiomers, substantially free of each other, are are included within the scope of the present invention. Be additionally, all the mixtures of the two are included enantiomers They are also included, within the scope of the present invention, polymorphs (polymorphic forms) and hydrates (hydrated forms) of the compounds of the present invention.

The present invention includes, within its scope, the prodrugs of compounds 1 and 2. In general, such types of prodrugs will be functional derivatives of the compounds of this invention, which are easily convertible, in vivo , into the required compound

The term "therapeutically amount effective "means the amount of a drug or agent pharmacist, which will obtain the biological or medical response of tissue, system, animal or human, that is being investigated, by by a researcher or by a doctor specialized in The clinical specialty.

As used here, in this document, the term "composition" is intended to cover a product  that understands the ingredients specified in the quantities specified, as well as any product that results, directly or indirectly, from the combination of the ingredients specified in the specified quantities.

In accordance with the present invention, the flibanserin 1, can be used as a monotherapy, or in conjunction with component 2, as a combination therapy. If flibanserin 1 is administered in combination with the component 2, 1 and 2 can be administered separately or together, in a pharmaceutical composition Additionally, in addition, the administration of an element of the combination of the present invention, may be carried out previously, at the same time, or subsequently to the administration of other elements of the combination.

Flibanserin 1 or the elements of the combination of 1 and 2, can be administered via administration  oral, parenteral (such as by injection or implant intramuscular, intraperitoneal, intravenous or subcutaneous), buccal, nasal, vaginal, rectal, sublingual, or topical (such as eye drops in the eyes), and can be formulated, alone or together, in dosage unit formulations appropriate, containing brackets, adjuvants and vehicles appropriate, non-toxic, and pharmaceutically acceptable, for each route of administration

Pharmaceutical compositions, forms of dosage, equipment as "kits" of parts, for the administration of 1 or 1 and 2 of the present invention, may present, in a convenient way, in unit forms of dosage, and can be prepared by any of the procedures that are well known by people experts in the specialized art of pharmacy. All the procedures, include the stage of bringing the active ingredient to an association with the support or vehicle, which is located consisting of one or more accessory ingredients. In a way General, pharmaceutical compositions, dosage forms, equipment as "kits", or parts, are prepared by proceeding to take active ingredients, to an association, with a support or liquid vehicle, or with a solid support or vehicle, finely divided, or both, in an intimate way and finally in case necessary, form the product, in the desired dosage form. In pharmaceutical compositions, the active compounds, are include in an amount sufficient to produce the desired pharmacological effect

Formulations, compositions, forms of dosage, or equipment as "kits" of parts that they contain 1 and / or 2, separately or together, which are appropriate for oral administration, may be in the form of discrete units, such as those consisting of hard capsules or soft, tablets, tablets or sideburns, containing, each of them, a predetermined amount of the active ingredients; in form of powdered materials or granules that can be pruned disperse; in the form of a solution or a suspension in a aqueous liquid or in a non-aqueous liquid; in the form of syrups or of elixirs; or in the form of an oil-in-water emulsion, or of an emulsion of the water-in-oil type.

The dosage forms intended for the oral use, can be prepared in accordance with any procedure known in the art of specialized technique for the manufacture of pharmaceutical formulations and such types of compositions

The excipients used may be, by example, (a) inert diluents, such as those consisting of the mannitol, sorbitol, calcium carbonate, pregeletinized starch, lactose, calcium phosphate or sodium phosphate; (b) granulating agents and disintegrants, such as povidone, copovidone, hydroxypropyl methylcellulose, corn starch, alginic acid, crospovidone, sodium starch glycolate, croscamellose, or potassium polacrilin; (c) binding agents, such as cellulose microcrystalline or acacia; and (d) lubricating agents, such as the magnesium stearate, stearic acid, fumaric acid or talcum powder.

In some cases, formulations for use oral, they can be in the form of hard gelatin or HPMC capsules, wherein, active ingredients 1 and / or 2, separately or together, they are mixed with an inert solid diluent, as per example, pregelatinized starch, calcium carbonate, phosphate calcium, or kaolin, or are dispensed via a granule formulation. These can also be in the form of soft gelatin capsules, where, the active ingredient is mixed with water or with a medium oily, such as peanut oil, liquid paraffin, medium chain triglycerides or olive oil.

The tablets, capsules or granules, can be of the uncoated type or these can be coated by techniques known, in order to delay disintegration and absorption, in the gastrointestinal tract and thereby provide an action delayed or sustained action, for another period of time long. Thus, for example, a material retardant of the time, such as cellulose phthalate acetate, or hydroxypropylcellulose succinate acetate, or a sustained release material, such as a copolymer of ethyl cellulose or ammonium methacrylate (type B).

The coated tablets can be prepared, correspondingly in accordance, by coating nuclei produced analogously to tablets, with substances normally used for coating tablets, as per example, collidone or shellac, gum arabic, talcum powder, titanium or sugar In order to achieve a delayed release or prevent incompatibilities, the core, may also consist in a certain number of layers. In a similar way, the tablet coating, may consist of a certain number or layers, in order to achieve a delayed release, of one possible way, using the excipients above mentioned above for tablets.

The liquid dosage forms, for the oral administration, include emulsions, solutions, pharmaceutically acceptable suspensions, syrups, and elixirs, containing inert diluents commonly used in the art of specialized technique, such as water. In addition to such types of inert diluents, the compositions, may also include adjuvants, such as wetting agents, agents emulsifiers and suspensions, and sweetening, flavoring agents (condiments), perfumes and preservatives.

Aqueous suspensions contain, normally, active materials 1 and / or 2, separately or together, in admixture with excipients suitable for manufacture of aqueous suspensions. Such types of excipients, they can be (a) suspending agents, such as the hydroxyethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and acacia gum; (b) dispersing or wetting agents, which may be (b.1) a phosphatide, such as lecithin, (b.2) a product of condensation of an alkylene oxide with a fatty acid, as per example, polyoxyethylene stearate, (b.3) a product of condensation of ethylene oxide with a chain aliphatic alcohol long, such as heptadecaethylene xyacethanol, (b.4) a condensation product of ethylene oxide with a partial ester, derived from a fatty acid, and a hexitol, such as monooleate from polyethylene-sorbitol, or (b.5) a product of condensation of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as, for example, polyoxyethylene sorbitan monooleate.

Aqueous suspensions, may also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl; one or more coloring agents; one or more flavoring agents (condiments); and one or more agents sweeteners, such as sucrose or saccharin.

Aqueous suspensions can be formulated proceeding to suspend active ingredients 1 and / or 2, for separately, or together, in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut, or in a mineral oil, such as liquid paraffin. The oil or oily suspensions, may contain an agent thickener, such as beeswax, hard paraffin, or alcohol  cetyl Sweetening agents and agents can be added flavorings or condiments, in order to provide a Tasty or appetizing oral preparation. These compositions can be prepared by adding an antioxidant, such as the ascorbic acid.

Dispersible powders and granules (granules), are suitable for the preparation of a aqueous suspension These provide the active ingredient 1 and / or 2, separately or together, in admixture, with a dispersing agent or humectant, a suspending agent and one or more preservatives. The dispersing or wetting agents and suspending agents, which are appropriate, exemplified by those already mentioned above They may also be present, additional excipients, such as, for example, agents sweeteners, flavorings (condiments) and dyes, previously described above.

Pharmaceutical formulations and compositions, dosage forms or equipment as kits, parts of the present invention, they can also be in the form of emulsions Oil-in-water type. The oil or oily phase can be a vegetable oil, such as olive oil or the oils of peanut, or a mineral oil, such as liquid paraffin, or a mix of these.

Appropriate emulsifying agents may be (a) gums of natural origin, such as acacia gum, and rubber tragacanth, (b) naturally occurring phosphatides, such as seed of soy and lecithin, (c) esters or partial esters derived from fatty acids and hexitol anhydrides, such as monooleate sorbitan, (d) condensation products of said esters partial with ethylene oxide, such as monooleate polyoxyethylene sorbitan. Emulsions, can also contain sweetening and flavoring agents or seasonings

Syrups and elixirs, can be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such types of formulations can also contain a preservative and a flavoring or seasoning, and agents dyes

Pharmaceutical formulations and compositions, dosage forms or equipment as kits, parts of the present invention, containing 1 and / or 2, separately or together, they can be in the form of a suspension or solution injectable, sterile, aqueous or oilseed. The suspension can be formulated in accordance with known procedures, using those dispersing or wetting agents, or agents of suspension, which have been mentioned above, above. The Injectable, sterile preparation may also be a solution or suspension for injection, sterile, in a diluent or solvent not toxic, paranterally acceptable, for example, as a solution in 1,3-toluene-diol. Between the acceptable vehicles and solvents that can be used, can mention water, Ringer's solution, and isotonic solution of sodium chloride. Additionally, in addition, as a solvent medium or of suspension, oils are used in a conventional manner set. For this purpose, any oil can be used soft fixation, including mono- or diglycerides synthetic Additionally, in addition, fatty acids, such as oleic acid, find its use in the preparation of injectable

Preparations in accordance with the present invention, containing 1 and / or 2, separately or jointly, for parenteral administration, they include solutions, suspensions, or emulsions, sterile, aqueous, or not aqueous.

Examples of solvents or vehicles do not aqueous, are propylene glycol, polyethylene glycol, vegetable oils,  such as olive oil, and corn oil, gelatin, and injectable organic esters, such as ethyl oleate. Such types of dosage forms, may also include adjuvants, such as those consisting of preservatives, agents humectants, emulsifying agents and dispersing agents. These they can be sterilized by, for example, filtering through a bacteria retention filter, by incorporating sterilizing agents in the compositions, by irradiation of the compositions, or proceeding to heat the compositions. These can also be manufactured in the form of solid compositions, sterile, which can be reconstituted in sterile water, or some other injectable, sterile medium, immediately before use. The combination of the present invention, can also be administered in form of suppositories for rectal administration. This composition, can be prepared by mixing the drugs, with an appropriate, non-irritating excipient, which is solid, at running temperatures, but liquid, at rectal temperature and, so, therefore, that will melt in the rectum, to release the drug. Such types of materials are cocoa butter, the hard fat, and polyethylene glycols. The compositions for the oral, nasal, or sublingual administration, are also prepared with standard excipients, which are well known, in the art specialized technique.

For topical administration, the formulations and pharmaceutical compositions, dosage forms or equipment a mode of "kits", of parts of the present invention, which contain 1 and / or 2, separately or together, can be formulated in liquid or semi-liquid preparations, such as liniments, lotions, applications; emulsions of the oil-in-water or water type in oil, such as creams, ointments, gels, or pastes, including toothpastes; or solutions or suspensions, such as drops, and the like.

The dosage of the active ingredients, in The compositions of the present invention can be varied. Do not However, the fact that the amount of flibanserin is necessary 1 for administration as a monotherapy, or of the active ingredients 1 and 2, for the administration of a therapy of combination, such that a dosage form is obtained appropriate. The selected dosage and dosage form, depend on the desired therapeutic effect, on the route or route of administration, and the duration of treatment. The margins of Dosage, in combination, are approximately corresponding to values ranging from one tenth, up to a portion of the clinically effective margins required to induce the desired therapeutic effect, respectively, when The products are used individually.

The beneficial effects of flibanserin 1, in the form of its free base, acid addition salts pharmaceutically acceptable and / or, optionally, in the form of hydrates (hydrated form) and / or solvates thereof, can be observed, regardless of whether the disturbance existed for a long time time, or if it had been acquired, and regardless of etiological origin (organic - of both types, physical and induced by drugs -, psychogenic, a combination of an organic origin - both physical and drug-induced, and psychogenic, or of origin unknown).

Within the present invention, flibanserin 1, is administered, preferably, in an amount such that, for an individual dosage, 5 to 200 mg of flibanserin 1. An amount corresponding to a value is preferred within a range of 10 to 150 mg, of a particularly preferably, from 20 to 100 mg of flibanserin 1. Appropriate dosage forms may contain, by example, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 mg of flibanserin 1. The values above mentioned, are based on flibanserin 1, in the form of the base free. If flibanserin 1 is applied in the form of its salts Acid addition, the corresponding values, are calculated easily from the aforementioned values.

Within the present invention, the agents antimuscarinics 2a, are administered, preferably, in an amount such that, per day, an amount comprised is applied within ranges ranging from 0.01 to 200 mg. Some are preferred amounts corresponding to a value within margins ranging from 0.5 to 100 mg of antimuscarinic agents 2a, preferring, in a particular way, values within a range of 1 to 50 mg of antimuscarinic agents 2a. The appropriate dosage forms, they may contain, for example, 0.01, 0.05, 0.5, 1, 2, 5, 10, 20, 25, 50, 100 or 200 mg of the antimuscarinic agents 2a. In a way advantageously, the compounds 2a, of the present invention, can administered in a single daily dose, or the dose Total daily, can be administered in two, three, or four times daily

Within the present invention, agonists of vasopressin 2b, are preferably administered in a amount such that, per day, an amount comprised is applied within ranges ranging from 0.01 to 100 mg. Some are preferred amounts corresponding to a value within margins ranging from 0.5 to 100 mg, from vasopressin agonists 2b, with particular preference being given to values within a range of 1 to 50 mg of vasopressin agonists 2b. The appropriate dosage forms, they may contain, for example, 0.01, 0.05, 0.5, 1, 2, 5, 10, 20, 25, 50, or 100 mg of vasopressin agonists 2b. In a way advantageously, the compounds 2b of the present invention can administered in a single daily dose, or the dose Total daily, can be administered in two, three, or four times daily

Within the present invention, modulators of serotonin / noradrenaline 2c, are administered, in a way preferably, in an amount such that, per day, a amount within a range of 0.01 to 200 mg Amounts corresponding to a value are preferred within a range of 0.5 to 150 mg of serotonin / noraderenaline 2c modulators, preferably, of a in particular, values within a range ranging from 1 to 100 mg of modulators of serotonin / noraderenaline 2c. The appropriate dosage forms, they may contain, for example, 0.01, 0.05, 0.5, 1, 2, 5, 10, 20, 25, 50, 100 or 200 mg of the serotonin / noraderenaline 2c modulators. Advantageously, the compounds 2c of the present invention, they can be administered in a single daily dose, or, the Total daily dose, can be administered in two, three, or four times daily

Within the present invention, agonists β3 2d, are preferably administered in a amount such that, per day, an amount comprised is applied within ranges ranging from 0.01 to 1000 mg. They prefer amounts corresponding to a value within margins ranging from 0.1 to 500 mg of the β3 2d agonists, with particular values being preferred within a range of 1 to 200 mg of β3 agonists 2d. Appropriate dosage forms may contain, by example, 0.1, 0.5, 1, 2, 5, 10, 20, 25, 50, 100 or 200 mg of the β3 2d agonists. Advantageously, the 2d compounds of The present invention can be administered in a single dose daily, or, the total daily dose, can be administered in two, three, or four times daily.

Another way of presenting this invention refers to the use of flibanserin combinations 1, optionally, in the form of the free base, the addition salts of pharmacologically acceptable acids and / or optionally, in the form of the hydrates (hydrated forms) and / or solvates thereof, and one or more, active ingredients 2, in a particular way, an ingredient active 2, optionally, in the form of acid addition salts pharmacologically acceptable, in the form of hydrates (forms hydrated) and / or solvates and, optionally, in the form of isomers individual optics, mixtures of the enantiomers or racemates of these, for the manufacture of a medicament for the treatment of any of the above mentioned disorders, above.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in Free base form, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicament for the treatment of any one of the aforementioned disorders, in combination with one or more, active ingredients 2, preferably with an ingredient active 2, optionally, in the form of acid addition salts pharmacologically acceptable, in the form of hydrates (forms hydrated) and / or solvates and, optionally, in the form of isomers individual optics, mixtures of the enantiomers or racemates of these.

Another way of presenting this invention refers to the use of flibanserin combinations 1, optionally, in the form of the free base, the addition salts of pharmacologically acceptable acids and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, and one or more antimuscarinic agents 2a, in a particular way, an agent antimuscarinic 2a, optionally, in the form of the addition salts of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of individual optical isomers, mixtures of the enantiomers or racemates of these, for the manufacture of a medicament for treatment of any of the disorders above mentioned above. Preferred antimuscarinic agents 2a, include tolterodine, oxybutynin, darifenacin, propiverine, solifenacin and tropsium.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicament for the treatment of any one of the disorders mentioned above, in combination with one or more antimuscarinic agents 2a, preferably, an antimuscarinic agent 2a, optionally, in the form of salts for the addition of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in form of the individual optical isomers, mixtures of the enantiomers or racemates of these. Preferred antimuscarinic agents 2a, include tolterodine, oxybutynin, darifenacin, propiverine, solifenacin and tropsium.

Another way of presenting this invention refers to the use of flibanserin combinations 1, optionally, in the form of the free base, the addition salts of pharmacologically acceptable acids and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, and one or more vasopressin 2b agonists, preferably, an agonist of vasopressin 2b, optionally, in the form of the addition salts of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of individual optical isomers, mixtures of the enantiomers or racemates of these, for the manufacture of a medicament for treatment of any of the disorders above mentioned above. A preferred vasopressin 2b agonist is the desmopressin

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicament for the treatment of any one of the disorders mentioned above, in combination with one or more vasopressin 2b agonists, preferably, a vasopressin 2b agonist, optionally, in the form of salts for the addition of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in shape of the individual optical isomers, mixtures of the enantiomers or racemates thereof. A vasopressin 2b agonist, Preferred is desmopressin.

Another way of presenting this invention refers to the use of flibanserin combinations 1, optionally, in the form of the free base, the addition salts of pharmacologically acceptable acids and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, and one or more serotonin / noradrenaline 2c modulators, one way preferable, a serotonin / noradrenaline 2c modulator, optionally, in the form of acid addition salts pharmacologically acceptable, in the form of hydrates (forms hydrated) and / or solvates and, optionally, in the form of isomers individual optics, mixtures of the enantiomers or racemates of these, for the manufacture of a medicament for the treatment of any of the above mentioned disorders, above. Preferred serotonin / noradrenaline 2c modulators include to venlafaxine, duloxetine, reboxentin and cizoliritine.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicament for the treatment of any one of the disorders mentioned above, in combination with one or more serotonin / noradrenaline 2c modulators, preferably, a serotonin / noradrenaline 2c modulator, optionally, in the form of acid addition salts pharmacologically acceptable, in the form of hydrates (forms hydrated) and / or solvates and, optionally, in the form of isomers individual optics, mixtures of the enantiomers or racemates of these. Preferred serotonin / noradrenaline 2c modulators, include venlafaxine, duloxetine, reboxentin and cizoliritine

Another form of presentation of the present invention relates to the use of combinations of flibanserin 1, optionally, in the form of the free base, pharmacologically acceptable acid addition salts and / or optionally, in the form of hydrates (hydrated forms ) and / or solvates thereof, and one or more β3 2d agonists, preferably, a β3 2d agonist, optionally, in the form of pharmacologically acceptable acid addition salts, in the form of hydrates (hydrated forms ) and / or solvates and, optionally, in the form of the individual optical isomers, mixtures of the enantiomers or racemates thereof, for the manufacture of a medicament for the treatment of any of the aforementioned disorders, above. Preferred β3 2d agonists include AD 9 67 7 /
TAK 677, CL 316, 243, SB 418790, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, trecanidine, Zeneca D7114, SR 59119, solabegron, CL616243, acid 2- [4- [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methyl-ethyl] amino] ethyl) phenoxy] 2-methylpropionic, BRL37344A and DGP-12177A.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicament for the treatment of any one of the disorders mentioned above, in combination with one or more β3 2d agonists, preferably, an agonists β3 2d, optionally, in the form of the addition salts of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of individual optical isomers, mixtures of the enantiomers or racemates of these. Preferred β3 2d agonists include a AD 9 67 7 / TAK 677, CL 316, 243, SB 418790, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, trecanidine, Zeneca D7114, SR 59119, solabegron, CL616243, acid 2- [4 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] -ethyl) phenoxy] 2-methylpropionic, BRL37344A and DGP-12177A.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, and one or more antimuscarinic agents 2a, preferably, an agent antimuscarinic 2a, selected from the group consisting of the  tolterodine, oxybutynin, darifenacin, propiverine, solifenacin and tropsium, optionally, in the form of acid addition salts pharmacologically acceptable, in the form of hydrates (forms hydrated) and / or solvates and, optionally, in the form of isomers individual optics, mixtures of the enantiomers or racemates of these, for the manufacture of a medicament for the treatment of overactive bladder syndrome

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicament for the treatment of the syndrome of the overactive bladder, in combination with one or more agents antimuscarinics 2a, preferably, an agent antimuscarinic 2a, selected from the group consisting of the  tolterodine, oxybutynin, darifenacin, propiverine, solifenacin and tropsium, optionally, in the form of acid addition salts pharmacologically acceptable, in the form of hydrates (forms hydrated) and / or solvates and, optionally, in the form of isomers individual optics, mixtures of the enantiomers or racemates of these.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, and one or more antimuscarinic agents 2a, preferably, an agent antimuscarinic 2a, selected from the group consisting of the  tolterodine, oxybutynin, darifenacin, propiverine, solifenacin and tropsium, optionally, in the form of acid addition salts pharmacologically acceptable, in the form of hydrates (forms hydrated) and / or solvates and, optionally, in the form of isomers individual optics, mixtures of the enantiomers or racemates of these, for the manufacture of a medicament for the treatment of Urinary incontinence urgently.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicine for the treatment of urgent urinary incontinence, in combination with one or more agents antimuscarinics 2a, preferably, an agent antimuscarinic 2a, selected from the group consisting of the  tolterodine, oxybutynin, darifenacin, propiverine, solifenacin and tropsium, optionally, in the form of acid addition salts pharmacologically acceptable, in the form of hydrates (forms hydrated) and / or solvates and, optionally, in the form of isomers individual optics, mixtures of the enantiomers or racemates of these.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, and the agonist of vasopressin 2b, desmopressin, optionally, in the form of salts for the addition of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in shape of the individual optical isomers, mixtures of the enantiomers or racemates thereof, for the manufacture of a medication for the treatment of bladder syndrome hyperactive

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicament for the treatment of the syndrome of the overactive bladder, in combination with the vasopressin agonist 2b, desmopressin, optionally, in the form of the addition salts of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of individual optical isomers, mixtures of the enantiomers or racemates of these.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in Free base form, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, and the agonist of vasopressin 2b, desmopressin, optionally, in the form of pharmacologically acceptable acid addition salts, in form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of the individual optical isomers, mixtures of the enantiomers or racemates thereof, for the manufacture of a Urinary incontinence medication urgently.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicine for the treatment of urgent urinary incontinence, in combination with the agonist of vasopressin 2b, desmopressin, optionally, in the form of salts for the addition of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in form of the individual optical isomers, mixtures of the enantiomers or racemates of these.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, and of one or more modulators of serotonin / noradrenaline modulators 2c, one preferable form, a serotonin / noradrenaline 2c modulator, selected from the group consisting of venlafaxine, duloxentin, reboxentin and cizoliritine, optionally, in the form of pharmacologically acceptable acid addition salts, in form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of the individual optical isomers, mixtures of the enantiomers or racemates thereof, for the manufacture of a medicine for urinary incontinence by stress.

Another way of presenting this invention refers to the use of flibanserin 1, optionally, in the form of the free base, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicine for the treatment of stress urinary incontinence, in combination with one or more modulators of serotonin / noradrenaline modulators 2c, one preferable form, a serotonin / noradrenaline 2c modulator selected from the group consisting of venlafaxine, duloxentin, reboxentin and cizoliritine, optionally, in the form of pharmacologically acceptable acid addition salts, in form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of the individual optical isomers, mixtures of the enantiomers or racemates thereof.

Another way of presenting this invention refers to the use of combinations of flibanserin  1, optionally, in the form of the free base, the addition salts of pharmacologically acceptable acids and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, and of one or more β3 2d agonists, preferably an agonist β3 2d, selected from the group consisting of AD9677 / TAK677, CL 316,243, SB 418790, L-796568, BMS-19 6 0 85, BRL-35135A, CGP12177A, BTA-243, GW 427353, trecanidine, Zeneca D7114, SR 59119, solabegron, CL616243, acid 2- [4 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] -ethyl) phenoxy] 2-methylpropionic, BRL37344A and DGP-12177A, optionally, in the form of pharmacologically acceptable acid addition salts, in form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of the individual optical isomers, mixtures of the enantiomers or racemates thereof, for the manufacture of a medicine for bladder syndrome hyperactive

Another way of presenting this invention refers to the use of flibanserin 1 optionally, in Free base form, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicament for the treatment of the syndrome of the overactive bladder, in combination with one or more agonists β3, 2d, preferably, a β3 2d agonist, selected from the group consisting of AD 9 67 7 / TAK 677, CL 316, 243, SB 418790, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GW 427353, trecanidine, Zeneca D7114, SR 59119, solabegron, CL616243, acid 2- [4 - [[(1S, 2R) -2-hydroxy-2- (4-hydroxyphenyl) -1-methylethyl] amino] -ethyl) phenoxy] 2-methylpropionic, BRL37344A and DGP-12177A, optionally, in the form of pharmacologically acceptable acid addition salts, in form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of the individual optical isomers, mixtures of the enantiomers or racemates thereof.

The examples given below, illustrate the present invention, without restricting the scope of is:

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Examples of pharmaceutical formulations

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2

We proceed to mix, together, the active substance, finely ground, lactose, and some of the starch corn. The mixture is screened, then humidified with a solution of polyvinylpyrrolidone in water, knead, and granulate in wet, and dries. The granules, the remaining corn starch, and the magnesium stearate, sifted and mixed together. The mix, compress, in order to produce tablets in a way and suitable size.

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4

We proceed to mix, together, the active substance, finely ground, some cornstarch, lactose, microcrystalline cellulose and polyvinylpyrrolidone, the mix, sieve and process with the rest of starch and water, to form a granulate, which is dried and sieved. He sodium carboxymethyl starch and stearate magnesium, they are added and mixed and the mixture is compressed to form tablets of the appropriate size.

5

We proceed to mix, together, the active substance, corn starch, lactose and polyvinylpyrrolidone, and mix carefully, thoroughly, and moisten with water. The wet mass is passed, pressing it, to through a sieve, with a size of maya of 1 mm, it is dried to a temperature of about 45 ° C and the granules are made pass, then, through the same screen. After what the magnesium stearate has been mixed, it proceeds to produce convex tablet cores, with a diameter of 8 mm, by compression process in a tablet production machine. The cores of tablets produced in this way are coated in a self-known form, with a coating, consistent, essentially, in sugar and talc. Coated tablets finished, they are polished with wax.

7

We proceed to mix, together, the active substance and corn starch, and moisten with water. The wet mass, sifted and dried. The dried granules are screened and Mix with magnesium stearate. The finished mixture is packaged in hard gelatin capsules, size 1.

8

The active substance is dissolved in water, at its own pH value or optionally, at a pH of 5.5 to 6.5, and sodium chloride is added, to make it isotonic. The solution obtained, filtered, free of pyrogens and, the filtrate, is transfers, under aseptic conditions, in ampoules, which are then sterilized, and sealed by fusion.

9

The hard fat melts. At a temperature of 40 ° C, the active substance is dispersed, in a way homogeneous This is cooled to a temperature of 38 ° C, and poured into suppository molds, slightly cooled.

G) Tablet coated with a film: Combination of flibanserin with 2nd Nucleus

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Covering

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H) Tablet coated with a film: Combination of flibanserin with 2b Nucleus

12

Covering

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I) Bilayer tablet coated with a film: Combination of flibanserin with 2c Nucleus

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Covering

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Claims (9)

1. Use of an effective amount of flibanserin 1 optionally, in the form of the free base, the addition salts of pharmacologically acceptable acids and / or optionally, in the form of the hydrates and / or solvates thereof, for the treatment or urinary incontinence prevention 2. Use of a combination of flibanserin 1 optionally, in the form of the free base, the addition salts of pharmacologically acceptable acids and / or optionally, in the form of the hydrates (hydrated forms) and / or solvates thereof, and one or more, active ingredients 2, optionally, in the form of the salts of addition of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in shape of the individual optical isomers, mixtures of the enantiomers or racemates thereof, for the manufacture of a medicine for the treatment or prevention of incontinence urinary 3. Use of flibanserin 1, optionally, in Free base form, acid addition salts pharmacologically acceptable and / or optionally, in the form of hydrates (hydrated forms) and / or solvates thereof, for manufacture of a medicine for the treatment of or prevention of urinary incontinence, any one of the above mentioned disorders, in combination with one more ingredients assets 2, optionally, in the form of the addition salts of pharmacologically acceptable acids, in the form of hydrates (hydrated forms) and / or solvates and, optionally, in the form of individual optical isomers, mixtures of the enantiomers or racemates of these. 4. Use according to any one of claims 1 to 3, characterized in that urinary incontinence is the overactive bladder syndrome. 5. Use according to any one of claims 1 to 3, characterized in that urinary incontinence is urgently needed. 6. Use according to any one of claims 1 to 3, characterized in that urinary incontinence is urgent urinary incontinence. 7. Use according to any one of claims 1 to 3, characterized in that urinary incontinence is stress urinary incontinence. 8. Use according to any one of claims 1 to 3, characterized in that the urinary incontinence is the combined urinary incontinence. 9. Use according to one or more of the claims 2 to 8, where active ingredient 2 is selected from among antimuscarinic agents 2a, vasopressin 2b agonists, serotonin / noradrenaline 2c modulators, and agonists β3 2d, optionally, in combination with an excipient pharmacologically acceptable.